Laura H. Corbit

Double Dissociation of Basolateral and Central Amygdala Lesions on the General and Outcome-Specific Forms of Pavlovian-Instrumental Transfer

This series of experiments compared the effects of lesions of the basolateral complex (BLA) and the central nucleus (CN) of the amygdala on a number of tests of instrumental learning and performance and particularly on the contribution of these structures to the specific and general forms of pavlovian-instrumental transfer (PIT). In experiment 1, groups of BLA-, CN-, and sham-lesioned rats were first trained to press two levers, each earning a unique food outcome (pellets or sucrose), after which they were given training in which two auditory stimuli (tone and white noise) were paired with these same outcomes. Tests of specific satiety induced outcome devaluation, and tests of PIT revealed that, although the rats in all of the groups performed similarly during both the instrumental and pavlovian acquisition phases, BLA, but not CN, lesions abolished selective sensitivity to a change in the reward value of the instrumental outcome as well as to the selective excitatory effects of reward-related cues in PIT. In experiment 2, we developed a procedure in which both the general motivational and the specific excitatory effects of pavlovian cues could be assessed in the same animal and found that BLA lesions abolished the outcome-specific but spared the general motivational effects of pavlovian cues. In contrast, lesions of CN abolished the general motivational but spared the specific effects of these cues. Together, these results suggest that the BLA mediates outcome-specific incentive processes, whereas CN is involved in controlling the general motivational influence of reward-related events.

Habitual alcohol seeking: Time course and the contribution of subregions of the dorsal striatum

BACKGROUND Addictions are defined by a loss of flexible control over behavior. The development of response habits might reflect early changes in behavioral control. The following experiments examined the flexibility of alcohol-seeking after different durations of self-administration training and tested the role of the dorsal striatum in the control of flexible and habitual alcohol self-administration. METHODS Rats were trained to lever-press to earn unsweetened ethanol (EtOH) (10%). The sensitivity of the lever-press response to devaluation was assessed by prefeeding the rats either EtOH or sucrose before an extinction test after different amounts of training (1, 2, 4, and 8 weeks). We subsequently tested the role of the dorsomedial striatum (DMS) and dorsolateral striatum (DLS) in controlling alcohol seeking with reversible inactivation techniques (baclofen/muscimol: 1.0/.1 mmol/L, .3 μL/side). RESULTS We find that operant responding for EtOH early in training is goal-directed and reduced by devaluation, but after 8 weeks of daily operant training, control has shifted to a habit-based system no longer sensitive to devaluation. Furthermore, after relatively limited training, when responding is sensitive to devaluation, inactivation of the DMS greatly attenuates the alcohol-seeking response, whereas inactivation of the DLS is without effect. In contrast, responding that is insensitive to devaluation after 8 weeks of training becomes sensitive to devaluation after inactivation of the DLS but is unaffected by inactivation of the DMS. CONCLUSIONS These experiments demonstrate that extended alcohol self-administration produces habit-like responding and that response control shifts from the DMS to the DLS across the course of training.

The General and Outcome-Specific Forms of Pavlovian-Instrumental Transfer Are Differentially Mediated by the Nucleus Accumbens Core and Shell

Tests of Pavlovian–instrumental transfer (PIT) demonstrate that reward-predictive stimuli can exert a powerful motivational influence on the performance of instrumental actions. Recent evidence suggests that predictive stimuli produce this effect through either the general arousal (general PIT) or the specific predictions (outcome-specific PIT) produced by their association with reward. In two experiments, we examined the effects of pretraining lesions (Experiment 1) or muscimol-induced inactivation (Experiment 2) of either the core or shell regions of the nucleus accumbens (NAC) on these forms of PIT. Rats received Pavlovian training in which three auditory stimuli each predicted the delivery of a distinct food outcome. Separately, the rats were trained to perform two instrumental actions, each of which earned one of the outcomes used in Pavlovian conditioning. Finally, the effects of the three stimuli on performance of the two actions were assessed in extinction. Here we report evidence of a double dissociation between general and outcome-specific PIT at the level of the accumbens. Shell lesions eliminated outcome-specific PIT but spared general PIT, whereas lesions of the core abolished general PIT but spared outcome-specific PIT. Importantly, the infusion of muscimol into core or shell made immediately before the PIT tests produced a similar pattern of results. These results suggest that whereas the NAC core mediates the general excitatory effects of reward-related cues, the NAC shell mediates the effect of outcome-specific reward predictions on instrumental performance, and thereby serve to clarify reported discrepancies regarding the role of the NAC core and shell in PIT.

General and outcome-specific forms of Pavlovian-instrumental transfer: the effect of shifts in motivational state and inactivation of the ventral tegmental area.

This study compared the contribution of the general activating and specific cueing properties of Pavlovian stimuli to Pavlovian‐instrumental transfer (PIT) and the role of the ventral tegmental area (VTA) in mediating these effects. In Experiment 1, hungry rats initially received Pavlovian training, in which three distinct auditory stimuli predicted the delivery of three different food outcomes. Next, the rats were trained to perform two instrumental actions, each earning a unique outcome selected from the three used in Pavlovian conditioning. Finally, the effects of the three stimuli on performance of the two actions were assessed in extinction. Presentation of a stimulus that had been paired with the same outcome as an action increased its performance relative to the other action, demonstrating that PIT effects can be outcome selective. In contrast, presentation of the stimulus that predicted the outcome that was not earned during instrumental training facilitated the performance of both actions indiscriminately. This effect, but not the outcome‐selective effect, was abolished by a shift from a hungry to a relatively sated state. Experiment 2 examined the effects of inactivation of the VTA on these two forms of PIT. VTA inactivation was found to attenuate PIT but, unlike satiety, did not appear to differentially affect the general or the outcome‐selective forms of PIT. The VTA appears therefore to play an important but general role in the initiation of instrumental actions, enabling cues to influence performance whether they enhance responding by changes in arousal or by retrieving particular actions based on their consequences.

Associative learning mechanisms underpinning the transition from recreational drug use to addiction

Learning theory proposes that drug seeking is a synthesis of multiple controllers. Whereas goal‐directed drug seeking is determined by the anticipated incentive value of the drug, habitual drug seeking is elicited by stimuli that have formed a direct association with the response. Moreover, drug‐paired stimuli can transfer control over separately trained drug seeking responses by retrieving an expectation of the drugs identity (specific transfer) or incentive value (general transfer). This review covers outcome devaluation and transfer of stimulus‐control procedures in humans and animals, which isolate the differential governance of drug seeking by these four controllers following various degrees of contingent and noncontingent drug exposure. The neural mechanisms underpinning these four controllers are also reviewed. These studies suggest that although initial drug seeking is goal‐directed, chronic drug exposure confers a progressive loss of control over action selection by specific outcome representations (impaired outcome devaluation and specific transfer), and a concomitant increase in control over action selection by antecedent stimuli (enhanced habit and general transfer). The prefrontal cortex and mediodorsal thalamus may play a role in this drug‐induced transition to behavioral autonomy.

Inactivation of the Lateral But Not Medial Dorsal Striatum Eliminates the Excitatory Impact of Pavlovian Stimuli on Instrumental Responding

Conditioned stimuli are important guides for behavioral actions. This experiment determined the role of the dorsal striatum in conditioned-stimulus modulation of instrumental responding using the pavlovian-instrumental transfer (PIT) paradigm. Rats received pavlovian training wherein two different auditory stimuli predicted the delivery of two food rewards. Next, rats were trained to perform two instrumental actions earning the same two rewards. Finally, the impact of pavlovian stimuli on instrumental performance was assessed in extinction: the stimuli were periodically presented while rats were free to perform the lever-press response. Before testing, medial or lateral dorsal striatum was infused with saline or bacolfen/muscimol, to temporarily inactivate the region. Under saline, outcome-selective PIT was observed: presentation of a stimulus paired with the same outcome as the instrumental action elevated responding, whereas presentation of a stimulus paired with a different outcome did not. Inactivation of the dorsolateral striatum dramatically reduced this effect. Inactivation of the dorsomedial striatum left intact the ability of reward-related stimuli to invigorate responding; however, the selectivity of the stimulus effect was lost (i.e., both stimuli excited responding). These results indicate that subregions of the dorsal striatum play distinct roles in stimulus modulation of instrumental performance with the lateral region being vital for reward-related stimuli to excite responding and the medial region being involved in the integration of stimulus-reward associations with specific response-outcome associations to produce selective responding. These findings identify new roles for the dorsal striatum in mediating the incentive effects of reward-predictive stimuli on behavioral actions made to obtain reward.

Posterior dorsomedial striatum is critical for both selective instrumental and Pavlovian reward learning

The dorsal striatum (DS) has been implicated in instrumental learning but its role in the acquisition of stimulus‐driven behaviour is not clear. To explore the contribution of the DS to both response‐outcome (R‐O) and stimulus‐outcome (S‐O) associative learning, we pharmacologically inactivated subregions (dorsolateral, anterior dorsomedial and posterior dorsomedial) of the DS during acquisition sessions in which subjects acquired two unique, novel R‐O pairs or two unique, novel S‐O pairs. To test whether specific R‐O or S‐O associations were learned under inactivation, rats were tested following selective‐satiety devaluation of one outcome under drug‐free conditions. In the instrumental task, control rats and rats with dorsolateral striatum (DLS) inactivation during learning responded less on the lever that had earned the devalued outcome than on the alternative lever at test, indicating that the DLS is not critical for the formation of R‐O associations. In contrast, rats with inactivation of the medial DS (DMS) (either anterior or posterior) during learning responded indiscriminately, suggesting failure to acquire the novel R‐O associations. In the Pavlovian task, both controls and rats with anterior DMS inactivation during learning responded less in the presence of the stimulus predicting the devalued outcome, whereas rats with DLS or posterior DMS inactivation during learning responded equally to the stimuli, indicating that they had not acquired the novel S‐O associations. These data confirm that the DLS and anterior region DMS mediate different aspects of reward‐related learning, and suggest that the posterior DMS may mediate a function common to both forms of learning (R‐O and S‐O). Finally, we demonstrate that both S‐O and R‐O associations are required for selective Pavlovian‐instrumental transfer.

Binge-Like Consumption of a Palatable Food Accelerates Habitual Control of Behavior and Is Dependent on Activation of the Dorsolateral Striatum

Access to highly palatable and calorically dense foods contributes to increasing rates of obesity worldwide. Some have made the controversial argument that consumption of such foods can lead to “food addiction,” yet little is known about how long-term access to highly palatable foods might alter goal-directed learning and decision making. In the following experiments, rats were given 5 weeks of continuous or restricted daily access to sweetened condensed milk (SCM) before instrumental training for food reward. Subsequently we examined whether goal-directed performance was impaired in these groups using the outcome-devaluation task. Control rats reduced responding following devaluation of the earned outcome as did those with previous continuous access to SCM. Of interest, rats with previous restricted access to SCM responded similarly under the devalued and nondevalued conditions, indicating loss of goal-directed control of responding. To identify whether the loss of goal-directed control was accompanied by differences in neuronal activity, we used c-Fos immunohistochemistry to examine the patterns of activation during devaluation testing. We observed greater c-Fos immunoreactivity in the dorsolateral striatum (DLS) and associated cortical regions in the group that received previous restricted access to SCM and demonstrated a lack of sensitivity to outcome devaluation. Infusion of the AMPA-receptor antagonist CNQX or dopamine D1-receptor antagonist SCH-23390 into the DLS before testing restored goal-directed performance in the restricted SCM group, confirming that this region is essential for habit-based performance. These results indicate that previous diet can alter subsequent learning and activity in the neural circuits that support performance.

Effects of Repeated Cocaine Exposure on Habit Learning and Reversal by N -Acetylcysteine

Exposure to drugs of abuse can result in a loss of control over both drug- and nondrug-related actions by accelerating the transition from goal-directed to habitual control, an effect argued to reflect changes in glutamate homeostasis. Here we examined whether exposure to cocaine accelerates habit learning and used in vitro electrophysiology to investigate its effects on measures of synaptic plasticity in the dorsomedial (DMS) and dorsolateral (DLS) striatum, areas critical for actions and habits, respectively. We then administered N-acetylcysteine (NAC) in an attempt to normalize glutamate homeostasis and hence reverse the cellular and behavioral effects of cocaine exposure. Rats received daily injections of cocaine (30 mg/kg) for 6 days and were then trained to lever press for a food reward. We used outcome devaluation and whole-cell patch-clamp electrophysiology to assess the behavioral and cellular effects of cocaine exposure. We then examined the ability of NAC to reverse the effects of cocaine exposure on these measures. Cocaine treatment produced a deficit in goal-directed action, as assessed by outcome devaluation, and increased the frequency of spontaneous and miniature excitatory postsynaptic currents (EPSCs) in the DMS but not in the DLS. Importantly, NAC treatment both normalized EPSC frequency and promoted goal-directed control in cocaine-treated rats. The promotion of goal-directed control has the potential to improve treatment outcomes in human cocaine addicts.

Habitual responding for alcohol depends upon both AMPA and D2 receptor signaling in the dorsolateral striatum

Chronic alcohol self-administration leads to alcohol-seeking behavior that is habitual and insensitive to changes in the value of the earned alcohol. Such behavior has been shown to rely on the dorsolateral region of the striatum in rats but the specific pharmacological control of output from this region is not yet understood. In the following experiments rats were trained to self-administer unsweetened 10% (v/v) ethanol in daily sessions for 8 weeks prior to testing for sensitivity to outcome devaluation. We examined the role of glutamatergic AMPA-receptor activation by testing the effects of the antagonist NBQX (0.3 and 1.0 μg/μl) infused specifically into the dorsolateral striatum (DLS) before devaluation testing. In a separate group of rats we examined the role of dopaminergic D2-receptor activation using the D2-receptor antagonist raclopride (0.2 and 1.0 μg/μl) infused into the DLS before devaluation testing. Following control (saline) infusions rats’ lever-press performance was insensitive to devaluation of ethanol thus showing evidence of habitual responding. NBQX and racolpride each restored goal-directed control of responding at doses that did not impair overall lever-press rates. These data demonstrate that expression of habitual alcohol seeking relies on glutamatergic inputs to the DLS and D2 receptors within the DLS.